Pascal Breton

Novel microparticulate system made of poly(methylidene malonate 2.1.2)

Formulation of PMM 2.1.2 microparticles entrapping ovalbumin as a model protein was achieved by using a double emulsion solvent evaporation method. Parameters such as the nature of the solvent, polymer concentration and polymer molecular weight were investigated. Preparation process led to the formation of spherical and smooth particles with a mean diameter of 5 microm, and an encapsulation efficiency and protein loading level of up to 16 and 2.9% w/w, respectively. After an initial burst of approximately 10%, the protein was released at a rate of less than 1% per day. This slow release kinetics of encapsulated ovalbumin in phosphate buffer indicates that most of the protein was encapsulated within the polymer matrix. Degradation of PMM 2.1.2 microparticles in the presence of esterases indicated that side chain hydrolysis of the polymer was the rate-determining step in bioerosion; cleavage of the ester side chain, which was further hydrolyzed to glycolic acid and ethanol, led to an acrylic acid and subsequent solubilization of the polymer. However, slow polymer backbone solubilization after degradation was observed.

In vitro and in vivo Evaluation of Poly(Methylidene Malonate 2.1.2) Microparticles Behavior for Oral Administration

The goal of this paper was to investigate the fate of novel poly(methylidene malonate 2.1.2) microparticles with different surface properties, i.e. prepared with or without polyvinylalcohol (PVA), after oral administration, using in vitro cell culture and an in vivo mice model. Incubation of particles with Caco-2 cells induced no cytotoxicity except for the microparticles prepared without PVA at high concentrations. At subtoxic concentrations, microparticles were highly associated to cells, independently of particles concentrations, particles surface properties (with or without PVA) or incubation time. Confocal microscopy analysis revealed that adsorption was the main phenomenon leading to the association of particles to cells. However, association was greater at 37°C than at 4°C, suggesting that an active process, such as endocytosis, could also occur. In vivo, radiolabeled particles were mainly found in luminal content and also adsorbed onto the epithelium. After 24 hours, more than 15% of PVA-free microparticles were still present in the gastrointestinal tract, compared to 5% for particles prepared with PVA. However, histological evaluation revealed low uptake of particles by Peyers patches. As a conclusion, this study provided a good correlation between in vitro and in vivo evaluation. These particles could be useful for oral sustained release and delivery of drugs to intestinal and colon epithelium.

Synthesis of new acylpseudopeptides analogous to n-acetylmuramyl dipeptide (MDP)

Abstract The synthesis of new non-glycosylated derivatives of MOP is described. Acylpseudopenta- or hexapeptides, of general formula R 1 ,-XxxΨ[CH 2 ,O]-D(L)-Ala-Ala-D-Glu[Lys(R 2 )-NHEt]-NH 2 were obtained in two configurational forms on the α-carbon of the pseudo-alanyl (or lactyl) residue. The A/-tenTiinal pan of these compounds (R 1 -XxxΨ[CH 2 O]- D(D-Ala) mimics some of the essential chemical functions of /V-acetylmuramic acid (Xxx = Gly or Ser) and is substituted either by a lauroyl, a f-butyloxycarbonyl or an acetyl moiety (R 1 ): R 2 ,is either an acetate counter-ion or a glycyl resi- due. The diastereoisomers were resolved by high performance liquid cromatography (HPLC) and their absolute configuration was determined by proton nuclear magnetic resonance (NMR) in dimethylsulfoxide (DMSO). This technique evidenced furthermore two hydrogen bonds present in the structure of MDP.

Conformational Studies of Poly(Methylidene Malonate 2.1.2)

Therapeutic and/or prophylactic efficiency of biologically active molecules depends of the control of drug delivery and targeting. Drug targeting may be performed using biodegradable nanoparticles for delivering therapeutic agents like liposomes or soluble macromolecular carriers. Methylidene malonate 2.1.2, i.e. ethyl-2-ethoxycarbonylmethylenoxycarbonyl acrylate (MM 2.1.2) have recently been studied in order to improve their ability to polymerize and to allow nanoparticles formation in an aqueous medial. Erosion and enzymatic bioerosion were suggested to occur at the nanoparticle surface, mainly because of the ester hydrolysis which generates free carboxyl groups and leads to soluble polymers. However this erosion process and its influence on nanoparticle are not well defined. In order to understand, at the molecular level, the influence of various parameters on their conformations, a molecular modeling study was started on Poly(methylidene malonate 2.1.2) (PMM 2.1.2) and derivatives.